Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2

Li, Xiaochun; Saha, Piyali; Li, Jian; Blobel, Günter; Pfeffer, Suzanne R.

doi:10.1073/pnas.1611956113

Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2

Journal Article · Mon Aug 22 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1611956113· OSTI ID:1330262

Li, Xiaochun ^[1]; Saha, Piyali ^[2]; Li, Jian ^[2]; Blobel, Günter ^[1]; Pfeffer, Suzanne R. ^[2]

Rockefeller Univ., New York, NY (United States)
Stanford Univ. School of Medicine, Stanford, CA (United States)

Export of LDL-derived cholesterol from lysosomes requires the cooperation of the integral membrane protein Niemann–Pick C1 (NPC1) and a soluble protein, Niemann–Pick C2 (NPC2). Mutations in the genes encoding these proteins lead to Niemann–Pick disease type C (NPC). NPC2 binds to NPC1’s second (middle), lumenally oriented domain (MLD) and transfers cholesterol to NPC1’s N-terminal domain (NTD). Here, we report the 2.4-Å resolution crystal structure of a complex of human NPC1–MLD and NPC2 bearing bound cholesterol-3-O-sulfate. NPC1–MLD uses two protruding loops to bind NPC2, analogous to its interaction with the primed Ebola virus glycoprotein. Here, docking of the NPC1–NPC2 complex onto the full-length NPC1 structure reveals a direct cholesterol transfer tunnel between NPC2 and NTD cholesterol binding pockets, supporting the “hydrophobic hand-off” cholesterol transfer model.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: Howard Hughes Medical Inst; Ara Parseghian Medical Research Fund; National Inst. of Health; National Inst. of Diabetes and Digestive and Kidney Diseases; American Diabetes Association

OSTI ID:: 1330262

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 36 Vol. 113; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
Ebola virus glycoprotein
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cholesterol trafficking
crystal structure

Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2

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